Proposal summaries
B1193 - Understanding the lifestyle molecular and genetic pathways that link womens reproductive function to healthy ageing - 23/06/2011
Aims and objectives of the programme
Broad aims of programme
The aims of the programme are to (i) understand the mechanisms that underlie the associations of women's reproductive characteristics (age at menarche, menstrual patterns, follicular activity, fertility, pregnancy and age of menopause and menopausal changes) with later risk for chronic complex diseases and their risk factors (obesity, hypertension, dyslipidaemia, hyperglyaceamia, insulin resistance, type 2 diabetes, coronary heart disease, stroke, osteoporosis, depression, breast density and breast cancer); (ii) to understand the role of women's reproductive health in healthy ageing and (iii) to determine the mechanisms for the intergenerational transmission of patterns of women's reproductive, cardiovascular, metabolic, skeletal and mental health.
The programme will bring together existing funded work of the PI and co-applicants that is concerned with pregnancy related changes and future cardiovascular, metabolic and bone health in offspring and mothers (project grants from US NIH, MRC, Wellcome Trust & BHF). In the first phase we will focus primarily on consolidating the work from these different projects (objective 1 of the first 5 years) in order to obtain a comprehensive picture of how pregnancy related changes affect a wide range of future health related outcomes in mother and offspring. In addition in the first 5 years we will obtain detailed repeatedly assessed phenotypic data (hormonal, vascular, metabolic, bone and DNA methylation changes) on a cohort of women (the mothers) as they go through the menopausal transition (from age 47-52 years). These new data will be used to address objectives 2-7 below and will provide the evidence based for understanding how oestrogen deficiency and menopausal changes influence ageing in general and specifically vascular, metabolic and muscular-skeletal ageing. With subsequent renewal of the programme , after the first 5 years, we would focus on the daughter's menstrual pattern, follicular activity and emerging fertility, as well as linking data on the mother's breast density from routine mammography and mental health outcomes to the main dataset.
Specific objectives of the first 5 years
We will:
1. Determine the extent to which pregnancy related weight gain, vascular and metabolic changes are related to the mother's and her offspring's future reproductive, vascular, metabolic and muscular-skeletal health.
2. Determine the pattern of changes in glucose, insulin, lipids, blood pressure, total and truncal fat and bone mineral density as women go through the menopausal transition and distinguish whether there is a specific menopausal effect over and above age related changes in these phenotypes.
3. Determine the hormonal, genetic, molecular and lifestyle pathways that underlie variation in age at menopause and variation in changes in vascular, metabolic and bone phenotypes over the menopausal transition.
4. Determine the association of different patterns of change in glucose, insulin, lipids, blood pressure and total and truncal fat over the menopausal transition with variation in postmenopausal carotid intima media thickness.
5. Establish the role of DNA methylation in determining the timing and magnitude of menopausal changes.
6. Determine the pattern of global and gene-specific (e.g. ESR1) DNA methylation patterns as women go through the menopausal transition.
7. Determine the consequences of menopause- related DNA methylation changes with respect to subsequent changes in vascular, metabolic and muscular-skeletal health.
Data requirements and new data collection
Objective 1 above will use existing data or data currently being collected (e.g. mums clinic and 17+ clinic fasting blood samples and assays) and brings together agreed work of the PIs in ALSPAC as funded by existing grants (NIH; MRC; BHF).
The remaining objectives will be addressed by collection of new data from a subgroup (~3000) of the ALSPAC mothers who fulfil the following criteria:
Age 47-49 years at start of new clinics (September 2010)
No previous history of hysterectomy or bilateral oophorectomy
Not known to have undergone natural menopause
Mothers fulfilling these criteria will be invited to attend annual clinics over a 4 year period (4 clinics in total) at which the following will be completed:
1. Completion of menstrual cycle & hormonal use questionnaire
2. Taking of a fasting blood sample
3. Measurement of weight, height, waist circumference and blood pressure
4. DXA scan - total & hip
The grant will request funds to complete the following on the blood samples:
1. Repeat assessment (at each clinic) of sex hormones, glucose, insulin and lipids
2. Global and gene specific DNA methylation patterns
B1192 - Effects of maternal vitamin D status in pregnancy on DNA methylation patterns at birth association with phenotypes - 23/06/2011
Objectives
To assess DNA methylation changes in cord blood in relation to maternal vitamin D status during pregnancy.
To investigate if changes in DNA methylation at birth predict phenotypes in childhood. Selected phenotypes could include: cognition/ADHD symptoms, asthma-related phenotypes and obesity.
If sample size adequate we could perform a mendelian randomization approach using maternal polymorphism associated with vitamin D levels.
B1190 - Epigenetic mechanisms stress exposure and eating disorders - 23/06/2011
AIMS
1. To estimate a twin model investigating the extent to which the covariance of PTSD and disordered eating is due to genetic and environmental influences.
a. It is hypothesized that additive genetic and unique environmental factors will significantly influence the variance of PTSD and disordered eating as well as their covariance.
2. To estimate a network model of genetic and psychosocial variables associated with PTSD and disordered eating among a sample of women.
a. It is hypothesized that many genetic and psychosocial variables will overlap with both PTSD and disordered eating.
3. To investigate whether maternal prenatal stress exposure is associated with offspring epigenetic changes and disordered eating.
a. It is hypothesized that maternal stress will be directly and indirectly associated with offspring disordered eating.
4. To investigate whether associations identified in Aim #3 apply to the etiology of substance use and depressive symptomatology as well as disordered eating.
a. It is hypothesized that both similarities and differences in DNA methylation patterns will be observed in the relations between maternal prenatal stress exposure and offspring disordered eating, substance use, and depressive symptomatology.
An overview of the study design to meet aims 3 and 4 can be found in the attached powerpoint file.
B1189 - Investigating associations between TSH-associated SNPs and birth outcomes/later academic IQ outcomes - 23/06/2011
Background
Maternal subclinical hypothyroidism in pregnancy is associated with impaired neuropsychological development of the child (1) and a number of other adverse outcomes for both mother and offspring (2, 3). The Endocrine Society's Clinical Practice Guidelines (4) recommend treatment with T4 for women found to have subclinical hypothyroidism, defined by a serum TSH concentration above the upper limit of the trimester-specific and assay-specific reference range, with a normal free T4 (FT4). This treatment has not been proven to improve neurological development of the child. However, the potential benefits are considered to outweigh the potential risks.
Using data on healthy pregnant women from the Exeter Family Study (EFSOCH), we recently showed that the PDE8B rs4704397 polymorphism, known to strongly associate with TSH levels in the general population, is associated with subclinical hypothyroidism in pregnancy(5). More recently, the international thyroid consortium has used meta-analysis of genome-wide association studies to identify a total of 10 genetic loci that are robustly associated with TSH levels, 9 of which are not associated with other phenotypes. Only 3 of these loci have been published. The manuscript of the latest meta-analysis is in preparation. Pre-publication analysis of these 9 SNPs in the EFSOCH pregnant women shows that the SNPs together explain 4.4% of the variation in maternal TSH levels at 28 weeks of gestation. Each additional unit of an allele score composed of the 9 SNPs was associated with a 0.1SD higher TSH level in pregnancy (P=8e-12; Figure 1; Table 1). The result was essentially unchanged when excluding women who tested +ve for TPO antibodies or when adjusting for child's genotype at the 9 loci.
Table 1: Association between allele score composed of 9 TSH-altering SNPs and maternal TSH levels in pregnancy (unpublished EFSOCH data).
Model*
N
Beta (per TSH-raising allele), SD units
SE
P-value
Allele count
813
0.121
0.018
4E-11
Allele score**
858
0.104
0.015
8E-12
Allele score TPO-Ab negative women only
794
0.113
0.015
1E-13
Allele score adjusted child genotypes
561
0.104
0.023
8E-06
*Linear regression with outcome =TSH level in pregnancy (inverse-normal transformation), with age and age-squared as covariables, excluding women on TF medication and non-Eur.
**Allele_score=Weighted_score*N_available_SNPs/Sum_weights_of_available_SNPs, where Weighted_score=W1*SNP1+W2*SNP2+W3*SNP3...etc. Weighted by effect size in EFSOCH study. Included women with up to 2/9 SNPs missing.
MAIN RESEARCH QUESTION:
Are SNPs which explain 4.4% of the variance in TSH levels in pregnancy associated with offspring birth weight and gestational age?
Aim and hypothesis
We propose to use this allele score and available phenotypes in ALSPAC to test the hypothesis that exposure to higher TSH levels in utero is associated with offspring birth weight and length of gestation. Rare, monogenic nonautoimmune hypothyroidism is associated with preterm birth and low birth weight (6).
To maximise statistical power, we will meta-analyse the ALSPAC data with data from the EFSOCH and HAPO studies. Using the measured TSH levels in the EFSOCH study, we will use the triangulation method to approximate a Mendelian randomisation analysis.
B1186 - Genome-wide copy number variation association studies of blood pressure and lung function - 16/06/2011
Background
The extent of copy number variation across the genome is still the subject of much debate although genome-wide maps of common copy number variation have now begun to emerge. Methods for detection and characterisation of both common and rare copy number variants are still far from perfect with no one approach to mining the genome optimal to detect all sizes of CNV. Consequently, there is still much to be learned about the extent and impact of this form of variation on human health and disease. Early studies of the role of common copy number variation in disease, including the Wellcome Trust Case Control Consortium (WTCCC) CNV project with which we were involved, suggest that much of this variation may already be well tagged by SNPs on the most recent genotyping platforms. However, rare and low frequency copy number variants, which are not expected to be tagged by common SNPs, have been shown to play a role in diseases such as autism and schizophrenia and the contribution of copy number variants to quantitative traits such as blood pressure and lung function is still largely unexplored. Algorithms have been developed that aim to utilise the raw allelic intensities from contiguous SNPs in SNP genotyping arrays to detect and quantify copy number variation. Although these detection approaches have raised substantial challenges, the most recent genome-wide SNP data allow improved detection of copy number through the inclusion of many more probes. Building upon recent experience and growing expertise in CNV analyses (1,2,3,4) and on data from other studies (listed in the following paragraph) which have approved collaborative CNV analyses we will undertake, we propose collaborative CNV studies of blood pressure & lung function together with ALSPAC investigators. These studies will help to gain the maximum benefit from newly available genome-wide association study data in ALSPAC, and will build upon the SNP association analyses that ALSPAC investigators plan to undertake.
Identifying the genetic determinants of lung function and blood pressure may lead to the identification of potentially modifiable intermediate phenotypes which can be targets for public health interventions. Analyses of CNV association with blood pressure and lung function will be undertaken to further the understanding of the genetic architecture of these traits. SNP association studies have demonstrated that very large sample sizes are necessary to detect variants with small effect sizes. The inclusion of 9000 ALSPAC individuals will substantially boost the power of our planned study (which currently includes data from adults in the Busselton Health Study (n ~1500, with 3600 expected in 2011) and the British 1958 Birth Cohort (n ~8000), children from the Raine study (n ~1500) and children & young adults from the Cardiovascular Risk in Young Finns Study (n ~2450)).
In a subset of individuals, robust findings from these analyses may be validated (either by experimental assay or by direct genotyping of tag SNPs if available), and followed up with breakpoint sequencing to fine-map the precise genomic location of the CNV. If it would appear appropriate and scientifically beneficial to include any ALSPAC participants at this stage, then this will be subject to a separate application.
Approaches
Louise Wain will work closely with Dave Evans or Nicholas Timpson in order to undertake the analyses as discussed below. In the first instance, the analyses would need to be run by Louise Wain, but the project aims also to develop this capacity at the University of Bristol. The analysis could be undertaken on the high performance cluster at the University of Bristol if, for example, Louise Wain were offered visitor status (or using a similar new £2m facility in Leicester, as you prefer). An alternative would be the provision of secured log in access to Bristol servers remotely. What ever the preferred mechanism, we would propose that Louise visits Bristol for regular meetings with a named ALSPAC investigator. This will be supplemented by project progress reports shared and discussed as required with all named co-applicants from both the University of Bristol and the University of Leicester.
Analysis of CNV using using SNP chip data requires the use of the raw X and Y intensities and/or derivatives of these (log R ratio and B allele frequency). Due to the inherent noisiness of this data, a key stage in the process of generating CNV genotype calls will be quality control (QC) and definition of a suitable filtering strategy (2).
Quality control (QC) will be applied to each dataset to exclude outlying samples on the basis of the SNP genotype data (e.g. those with substantial missing genotype data, or showing ancestral differences in principal components analysis (PCA)) or intensity data (large standard deviations of genome-wide intensity measures and subsets of samples that might have been processed differently identifiable as likely batch effects by PCA). There are several algorithms available for detecting and measuring copy number variation in SNP genotyping data (e.g. QuantiSNP and PennCNV which are based on Hidden Markov Models) using the raw allelic intensities or derivations thereof. Raw CNV calls will be subject to further rigorous QC with filtering thresholds defined by simulation and sensitivity analyses undertaken to evaluate the consequences of the filtering strategy chosen on the downstream association testing.
CNVs will be tested for association with blood pressure variables, SBP and DBP, and lung function variables, FEV1 and FEV1/FVC, using linear regression. In addition, previously published CNV maps will be used to define boundaries of common CNVs and these CNVs will be tested for association using methods such as CNVtools. Validation will be undertaken in selected subsamples from these studies.
Additional benefit
The CNV methods, or calls used, could be applied to the study of a wide range of additonal phenotypes in ALSPAC and the experience of these kinds of analyses will benefit analysts involved in ALSPAC.
Genotype data required
This project requires the intensity data for each SNP and non-polymorphic probe on the array (log R ratio and B allele frequency, and raw X and Y intensities if possible).
References:
1. L. V. Wain, J. A. Armour, M. D. Tobin, Lancet 374, 340 (Jul 25, 2009).
2. L. V. Wain et al., PLoS One 4, e8175 (2009).
3. N. Craddock et al., Nature 464, 713 (Apr 1, 2010).
4. H. M. Blauw et al., Hum Mol Genet 2010, 10 (Aug 10, 2010).
B1185 - ALSPAC Ethics and Law Committee the first 16 years of ethical protection for an epidemiological birth cohort - 16/06/2011
I have been systematically working through the early ALSPAC Ethics and Law Committee documents for the ALSPAC Archive which is to be housed in the University of Bristol Library Special collections (alongside the Brunel collection and Penguin books). I am now thoroughly familiar with this material and would value time to write up the extent of the committee's early work. I propose to write a brief monograph which will systematically describe and classify the work of the committee during its first 16 years when the study participants reached an important legal milestone, summarising the ethical issues, discussion and outcomes and putting the committee's work into the legal and ethical context of the time. After appropriate review, I would hope to submit this to the Leverhulme Trust who have provided funding for work on the ALSPAC Ethics archive.
The Committee is considered by many as innovative, not only as it was the first ethical committee set up to provide legal and ethical advice for such a longitudinal study but also as ALSPAC was designed from the outset to utilise genetic data. In contrast to clinical genetics, the ethical issues generated in the context of such a population study had hardly been addressed previously.
The Committee has influenced other longitudinal epidemiological studies since its inception, e.g. UKBiobank, which modelled its Ethics and Governance Council on the ALSPAC Committee, the National Children's Study in the USA to which I attended an early ethics advisory workshop and the Swiss Etiological Study of Adjustment and Mental Health (which failed spectacularly).
My specific goals would be:
* To document the extent of the work of the committee through systematic analysis of the minutes of the meetings and accompanying documents. This will include research that the committee initiated; the three year Wellcome funded qualitative study designed to elicit the 8 year old participants' attitude to the use of their data in genetic research (Ethical Protection in Epidemiological Genetic Research: Participants' Perspectives).
* To select topics of particular importance that the committee discussed on many occasions, not only as the children grew up but also as legal and ethical practices changed (e.g. consent, disclosure of results, genetic analyses, record linkage, open access to data). Trace the development of these discussions and the recommendations made.
* To outline the committee's influence beyond that of the cohort e.g. advice to the UK House of Lords Select Committee, the Human Genetics Commission, the Nuffield Trust and European Society of Human Genetics.
I have the opportunity to spend two months next year (September 2012 - October 2012) at the Brocher Foundation (http://www.brocher.ch), a Swiss non-profit making foundation that provides facilities for visiting junior and senior researchers to write books, articles, essays, or PhD theses on the ethical, legal and social implications of medical research.I was encouraged to apply for a 2 month visiting researcher position but thought I had absolutely no chance of being accepted as most of the current visiting researchers are relatively senior academics.I am now somewhat embarrassed at putting the proposal to the Executive committee without previous discussion and apologise for this.I do feel it would be an excellent opportunity and anticipate with careful planning, my workload can be organised so as not to disrupt the ethical process within ALSPAC.I would of course make up the hours in whatever seems the most useful way; perhaps working full time instead of half time before and/or after the proposed absence.I hope the Executive feel able to support me in this development opportunity in my other role within the School by allowing the necessary flexibility of my working hours.
B1184 - Life course inequalities in asthma estimating its burden and understanding its aetiology - 16/06/2011
The complete project (submitted for a Wellcome Trut Intermediate Clinical Fellowship) includes an international collaboration with other birth and adult cohorts. This outline refers to the analysis that will be carried out with Alspac data.
AIMS
The purpose of this research is to describe the magnitude of inequalities in asthma phenotypes throughout the life course, identify the mechanisms that underlie them and thus provide means of reducing the burden of disease, both overall and in terms of contributing to avoidable health inequalities, due to this condition. The specific aims are:
1) Describe the socioeconomic inequalities in wheezing, asthma phenotypes, atopic makers, lung function and bronchial responsiveness in childhood and/or adolescence in Alspac.
2) Describe the life course socioeconomic inequalities in asthma phenotypes across generations: parents and offspring.
3) To determine the major causes of different socioeconomic patterns in asthma phenotypes identified in objectives 1 and 2.
4) Invetigate the role of health selection in asthma inequalities: determine whether asthma phenotypes influence socioeconomic position in children (schooling)
5) Investigate the role of health services role in asthma inequalities in children.
B1183 - Genetic studies of hip structure in ALSPAC mothers and children - 16/06/2011
Background
Several previous studies have examined the genetic basis of osteoporosis, by analysing associations between bone mineral density (BMD) as measured by DXA and genetic markers, including GWA studies in which several markers have been identified that appear to replicate across a range of cohorts 1. These studies have generally focussed on lumbar spine and hip BMD, which sites are the most widely used in terms of clinical tests for osteoporosis. Moreover, hip BMD is related to future risk of hip fracture, arguably the most important consequence of osteoporosis.
Hip structural analysis has been developed as a means of extracting information from hip DXA scans related to overall geometry and strength, and may provide further information beyond BMD with respect to future risk of fracture. Moreover, genetic factors which influence hip geometry may be different to those that affect BMD. Having previously used this approach to evaluate the influence of puberty on hip structure in ALSPAC children 2, we are now keen to apply it to identify possible genetic determinants thereof. Given that hip structural data will be available in both ALSPAC mothers and children, we will have an opportunity to compare and contrast genetic influences at the time hip development is approaching completion, with those in older adults, when hip structure is starting to be affected by age-related deterioration.
Aims
We aim to perform GWA studies (with replication) intended to identify genetic influences on hip structure in (i) adolescents approaching skeletal maturity (ALSPAC YP age 17) and (ii) older adults (ALSPAC mothers).
B1181 - Selection bias and health inequalities research - 09/06/2011
Do non-participation and drop-out from cohort studies bias estimates of socioeconomic inequalities in health?
Individuals of lower socioeconomic position (SEP) may be less likely to consent to participation at the start of a cohort study and more likely to drop out over time.1,2 It has also been shown in several cohorts that participants tend to be healthier than non-participants.1,2
Scandinavian studies exploiting record linkage have shown that despite cohorts being a relatively wealthy and healthy sample of the population, exposure-outcome associations are not biased by this selection, at least for certain well established relationships.2 Within ALSPAC, there is evidence that the prediction equations for measures of disruptive behaviour do not differ between i) individuals who were eligible to participate but did not consent to the study, ii) those who consented but dropped-out before the age of 8 years, and iii) those who continued to participate at 8 years3, again suggesting that selection bias may not affect estimates of exposure-outcome associations. It is not known, however, whether this is true when estimating socioeconomic inequalities in health. Since continued participation in the cohort is likely to be associated with both high SEP and better health, this may lead to estimates of health inequalities at later ages being underestimates.
Aim 1: To investigate whether nonparticipation and drop-out from cohort studies leads to underestimates of socioeconomic inequalities in health
We will make use of a set of outcomes for which data is available for (almost) the full cohort:
1. Perinatal factors: birth length, birth weight, gestational age at delivery, breastfeeding
2. Maternal factors: maternal obesity, maternal smoking during pregnancy
3. Child factors from routine data: Educational attainment at key stages 2 and 3
First, we will examine the association between these outcomes and participationat various stages of the cohort (e.g. attendance at the Focus@9 clinic and the Teen Focus 3 clinic) to explore whether those who participate at each stage have favourable levels of each outcome compared with those who do not participate. For educational attainment, we will also be able to explore whether those who consented to participate at the start of the study have different educational attainment compared to eligible children identified from the National Pupil Database who have never participated.
Next, we will calculate the socioeconomic inequality in each of these outcomes in the full ALSPAC cohort, using maternal education as the measure of SEP. We will then restrict our analysis firstly to those who attended the Focus@9 clinic, and second to those who attended the Teen Focus 3 clinic. For each of these restricted samples, we will again calculate an estimate of the association between maternal education and each outcome. We will be testing the hypothesis that our estimates of socioeconomic inequalities will attenuate towards the null as the sample gets more and more selected.
We will formally test whether the association between maternal education and each outcome differs between those who do and do not participate at each stage, using tests for interaction. We will then carry out sensitivity analysis to assess how different the associations would have to be between participants and non-participants for our analyses to lead to very different conclusions.
Aim 2: To identify whether problems caused by selection bias for the estimation of health inequalities are aggravated by using a categorical SEP indicator
The indicator of SEP most frequently used in epidemiological studies is maternal education. Within ALSPAC, we tend to use a four category variable - less than O-Level, O-Level, A-Level, and Degree or higher. This four category variable is unlikely to be capturing all of the very broad concept of SEP; it is possible that within each category of maternal education, those who drop out are actually of lower SEP. If so, this would result in the observed socioeconomic inequalities being an underestimate.
Our first step towards exploring this issue will be to examine whether, within each of the four categories of maternal education, there is an association between drop-out from the cohort and other measures of SEP (income, household social class, etc).
Subsequently, we will construct a multi-dimension measure of SEP using several variables (income, household social class, car ownership, index of multiple deprivation, reported financial difficulties, maternal age and parity, etc) using factor analysis. This SEP construct should be able to more finely differentiate between participants than maternal education alone can. We will then repeat the analysis outlined above for Aim 1, using this latent construct of SEP as the exposure instead of maternal education. That is, we will examine whether we still see an attenuation of estimates of inequality in the (almost) fully observed outcomes as the sample gets more and more restricted when using this latent construct of SEP.
B1180 - Multiple Risk Behaviours in Adolescence - 09/06/2011
We are requesting access to the age data on these variables at age 15-16 in order to undertake initial descriptive analyses of the all of the behaviours separately, followed by more complex analyses exploring the extent to which and ways in which these behaviours cluster using multiple regression, adjustment for missing data using multiple imputation techniques, and use of various latent variable techniques. The work is being undertaken as part of the DECIPHer programme of work on multiple risk behaviours in adolescence.
The work is directed by a multi disciplinary group of researchers, led by Prof Rona Campbell and Prof Matt Hickman, with involvement from Dr Ruth Kipping, Dr Jon Heron and Dr Kate Tilling. Dr Georgie MacArthur (Clinical Lecturer/public health trainee) will undertake the initial descriptive analysis and we are in the process of employing a Research Assistant to work full-time on this analysis. We would hope that both Georgie MacArthur and the RA would have direct access to the data and would be supported by Jon Heron and hence there would be no need to incur the time (and therefore costs) of a data buddy to facilitate the use of the data.
Following the initial analysis of data at ages 15-16, we will submit a separate application to the ALSPAC Executive for antecedent characteristics or exposures earlier in life; risk behaviours at other ages during adolescence; and outcomes such as education, morbidity and mortality.
B1178 - Following up findings from a genome-wide association study of attention-deficit hyperactivity disorder and associated conduct - 09/06/2011
Project outline:
A genome-wide association study of ADHD using antisocial behaviour as an index of heterogeneity
Introduction
ADHD is a highly heritable disorder that is of unknown pathogenesis (Stergiakouli & Thapar, 2010; Faraone et al, 2005). ADHD shows clinical as well as aetiological heterogeneity and the presence of antisocial behaviour (ASB) in children with ADHD is known to be an important marker of heterogeneity. It indexes greater clinical severity, poorer outcome, persistent problems in adulthood, stronger association with neurocognitive deficits and higher familial and genetic loading. Previous candidate gene studies have also suggested that the presence of ASB indexes heterogeneity (Langley et al, 2010).
In our ADHD programme grant we set out to identify ADHD susceptibility genes and also test for the effects of comorbid conduct disorder symptoms.
We have recently completed the genome-wide association study in a well-characterised sample of 727 children with DSM-IV/III-R diagnosed ADHD and 5,081 controls. We have tested for association between 1) SNPs and ADHD, 2) SNPs and Conduct disorder in children with ADHD.
B1177 - Collection of Objective Nicotine Exposure Biomarker Data in the Avon Longitudinal Study of Parents and Children - 09/06/2011
Project outline:
The primary objective of the proposed research is the collection of biological samples for future cotinine analysis in ALSPAC. We have collected smoking behaviour on the offspring at regular intervals from age 8/9, and we are now planning the collection of further data at age 20/21.
We propose to begin data collection in October 2011. Postal urine collection kits for cotinine analysis will be sent to the ~5,000 individuals on whom we have smoking status data for at least one previous assessment point at either age 15/16 or 17/18.
We anticipate a period of ~6 months to send out and receive collection kits. We will then seek follow-on funding from the Cancer Research UK Population and Behavioural Sciences Committee to support cotinine analyses.
Cancer Research UK Tobacco Advisory Group have agreed to fund the collection of postal samples for subsequent analyses, and invited us to apply for follow-on funding once the response rate has been established.
These data will be a resource for subsequent analyses. As a first step, we will use these data, together with similar data collected at age 15/16 and 17/18 to characterise smoking initiation trajectories with greater precision than is possible using self-reported smoking behaviour data.
These derived variables will also be incorporated into the ALSPAC data set for future secondary analyses.
B1176 - The impact of breast feeding on BMI growth trajectories among FTO gene carriers - 09/06/2011
The impact of breast feeding on BMI growth trajectories among FTO gene carriers
B1175 - Development of a phenome scan using ALSPAC data - 02/06/2011
This is a follow up to project B173 which was approved but not funded.
B1174 - Sequellae of Early Antibiotic Exposure in Children - 02/06/2011
As described in our scientific outline, the ALSPAC is uniquely suited to answer our research question. The detail on early exposure (including exposure to perinatal antibiotics), the meticulous documentation of growth, the availability of genetic data, as well as the large sample size make the ALSPAC data the source of choice for our work.
B1173 - Defining endotypes of childhood wheezing to elucidate underlying mechanism and genetic predisposition - 02/06/2011
The STELAR collaboration was established by Asthma UK to harmonize data collection on asthma and related allergic outcomes in five UK birth cohorts (ALSPAC, Manchester Asthma and Allergy Study, Isle of Wight Study, Ashford Study, Aberdeen SEATON study). A previous MRC grant funded data collection sweeps in three of these studies (IoW, MAAS and SEATON). This proposal is primarily to use machine learning tools (in collaboration with Microsoft, Cambridge) to develop novel phenotyping methods to better understand the endophenotypes of asthma.
B1149 - Genome-wide association of reading and language abilities in the normal population - 27/05/2011
Readingis one of the most important cognitive skills to develop as it lays the foundation for acquisition of other scholastic skills. While skilled reading involves perceptual processes and comprehension of text, this project focuses on processes related to accessing stored information about the meaning and pronunciation of words. Children's phonological memory might contribute directly to vocabulary acquisition (Gathercole, Willis, & Baddeley, 1991); in particular, specific language impairment (SLI) has been related to deficits in verbal short term memory as measured by a nonword repetition task which requires meaningless sequences of speech sounds to be repeated (Newbury, Bishop, & Monaco, 2005). Like reading measures, variation in nonword repetition is heritable, and limitations in phonological short term memory also influence dyslexia(Shaywitz & Shaywitz, 2005). Therefore, our study assesses the genetic influence of single nucleotide polymorphisms (SNPs) on both reading and language measures.
We have undertaken a genome-wide association study (GWAS) of reading and language traits using ~2.5 million SNPs (imputed from the Illumina 610 Bead chip) in 1200 individuals (aged 12 - 25 years). The reading measures include a reading factor derived from the Components of Reading Examination (Bates, et al., 2004), the Schonell Graded Word Reading Test and the National Adult Reading Test. The language measure was the summed score of two non-word repetition tests (Baddeley & Gathercole; Dollaghan & Cambell).
To complete our study we would like to attempt replication of our suggestively significant SNPs from the GWAS (none reach GWAS significance) to confirm whether these SNPs are true findings. The ALSPAC sample is a perfect replication sample because they measure reading in a similar aged sample and non-word repetition (our language measure) at a younger age. We therefore require beta effects, standard errors and p-values for the associations of 42 SNPs (33 reading, 9 language). These results will be included in our publication.
Bates, T. C., Castles, A., Coltheart, M., Gillespie, N., Wright, M. J., & Martin, N. G. (2004). Behaviour genetic analyses of reading and spelling: a component processes approach. Australian Journal of Psychology, 56, 115-126.
Gathercole, S. E., Willis, C., & Baddeley, A. D. (1991). Differentiating phonological memory and awareness of rhyme: Reading and vocabulary development in children. British Journal of Psychology, 82, 387-406.
Newbury, D. F., Bishop, D. V., & Monaco, A. P. (2005). Genetic influences on language impairment and phonological short-term memory. Trends Cogn Sci, 9(11), 528-534.
Shaywitz, S. E., & Shaywitz, B. A. (2005). Dyslexia (specific reading disability). Biol Psychiatry, 57(11), 1301-1309.
B1171 - Blood pressure regulation according to obesity status in childhood - 26/05/2011
Background and objective: The relationship between blood pressure and obesity is well established in both children and adults. Higher blood pressure levels are observed in obese individuals and increased blood pressure levels during childhood strongly predict hypertension in adults. Therefore, isolating genetic variations that may influence blood pressure according to obesity status at childhood might have major implications for public health. Among numerous genetic investigations on blood pressure and hypertension, the most frequent associations concerned the long arm of chromosome 2. Therefore, we in-depth investigated this region, in two independent French normal weight and obese pediatric populations.
B1169 - Replication of genetic loci for myopia loci at 15q14 and 15q25 - 26/05/2011
Locus 1 (15q14). We completed a GWAS for the phenotype 'refractive error' in our Discovery cohort, the population-based Rotterdam Study (N = 5,328 subjects, using SNPs genotyped with the Illumina Infinium II HumanHap550 chip v3.0 array) . The results were replicated in 4 additional cohorts (combined N = 10,280 individuals in the replication stage): the Rotterdam Study II cohort, the Rotterdam Study III cohort, the Erasmus Rucphen Family (ERF) Study cohort and the TwinsUK cohort. The findings have been reported [1].
Locus 2 (15q25). In collaboration with the TwinsUK group, a second region of strong association was observed at 15q25. This association was replicated in a combined sample comprising the above cohorts, along with subjects from the 1958 British Birth Cohort and the Australian Twin Eye Study cohort (combined N = 13,414 subjects). These findings have also been published [2].
We propose to carry out additional replication studies for 19 SNPs in these two regions of strong association in a number of cohorts of European ethnicity. The ALSPAC cohort is suitable because it is ethnically well-matched to our original study cohort and is also a population-based sample, not selected based on eye phenotypes. We expect this will aid the differentiation of causal variants and non-causal variants in the associated regions.
Replication analysis on the 19 SNPs will be performed by Dr Jez Guggenheim, who is part of the ALSPAC Myopia team, and summary results will be sent to Dr Virginie J.M. Verhoeven. To facilitate the replication step on the ALSPAC side, we ask for a DTA of the 19 SNPs to Dr Jez Guggenheim who will perform the work at Cardiff University, or in Bristol if required.
B1165 - Neurocognitive function and non-clinical psychotic symptoms in children and adolescents - 20/05/2011
The ALSPAC data proves a unique opportunity to explore the longitudinal relations between psychopathology and cognitive functioning and possible influences on these relationships of other psychopathology.